WO2021018085A1 - Procédé de préparation d'un dérivé d'hexahydrofurofuranol et d'intermédiaire du dérivé et procédé de préparation associé - Google Patents

Procédé de préparation d'un dérivé d'hexahydrofurofuranol et d'intermédiaire du dérivé et procédé de préparation associé Download PDF

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WO2021018085A1
WO2021018085A1 PCT/CN2020/104791 CN2020104791W WO2021018085A1 WO 2021018085 A1 WO2021018085 A1 WO 2021018085A1 CN 2020104791 W CN2020104791 W CN 2020104791W WO 2021018085 A1 WO2021018085 A1 WO 2021018085A1
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acid
group
formula
compound
prepared
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PCT/CN2020/104791
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English (en)
Chinese (zh)
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刘声民
林荆鑫
郑辉
叶美其
高照波
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浙江九洲药业股份有限公司
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Publication of WO2021018085A1 publication Critical patent/WO2021018085A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to the field of medical synthesis, in particular to a preparation method of hexahydrofurofuranol derivatives, its intermediates and a preparation method thereof.
  • R 1 is alkyl or arylalkyl and R 2 is alkyl or arylalkyl;
  • the present invention prepares (3R,3aS,6aR)-hexahydrofuro[2,3-b]-3-ol and hexahydrofuro[2,3-b]- through condensation, deprotection and cyclization reaction.
  • the report of the preparation method of 3-alcohol is basically in a blank state. The method is simple to operate, has relatively high output, and has strong applicability for industrial scale-up production. This method has brought tremendous help to both the economic benefits of drug synthesis and the operation process.
  • the method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol and -hexahydrofuro[2,3-b]-3-ol of the present invention is based on methoxy
  • the base alcohol reaction was started, and a method for preparing key intermediates for darunavir, which was different from the starting materials in the existing patent applications, was researched and developed.
  • the preparation method of the invention has low cost and mild reaction conditions, and provides another route suitable for industrialization for the preparation of the key intermediate of darunavir.
  • the present invention provides the following technical solutions:
  • the first aspect of the present invention provides an intermediate compound for the preparation of (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol, the structural formula is as follows:
  • R 1 and R 2 are hydrogen or hydroxy protecting groups
  • R 3 is alkyl, acyl, ether, ester or aryl
  • X is oxygen, sulfur or nitrogen.
  • the hydroxy protecting group is alkyl, silyl, C 2-11 acyl, C 4-9 cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl, C 2-11 Ether group, C 2-11 ester group
  • the silyl group is a tetramethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a tri-n-butylsilyl group, and a tert-butyldimethylsilyl group
  • the alkyl group is a C 1 -C 8 alkyl group
  • the aryl group is a phenyl group, a furyl group, a thienyl group or an indolyl group
  • the second aspect of the present invention provides a method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol formula IV, which consists of a compound of formula II' in the presence of an acid through a ring Synthesis reaction preparation,
  • R 2 , R 3 , and X are the same as above;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid.
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the third aspect of the present invention provides a method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol formula IV.
  • the compound of the above formula II is used in acid, alkali or metal catalyst
  • the compound of formula II' is prepared by deprotection in the presence of conditions, and then prepared by cyclization of the compound of formula II' in the presence of acid,
  • R 1 , R 2 , R 3 , and X are the same as above;
  • the base in the deprotection step is an organic base or an inorganic base
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the fourth aspect of the present invention provides a method for preparing (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]-3-ol formula IV, which consists of a compound of formula I undergoing condensation reaction in the presence of an acid
  • the compound of formula II is prepared, and the compound of formula II is prepared by deprotection in the presence of acid or base to obtain the compound of formula II', which is then prepared by cyclization of the compound of formula II' in the presence of acid,
  • R 1 , R 2 , R 3 , and X are the same as above.
  • the organic acid in the condensation reaction step is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid, and the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, and sulfuric acid , Phosphoric acid, aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, preferably p-toluenesulfonic acid;
  • the reaction temperature of the condensation reaction step is 10-50°C, preferably 15-35°C;
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzene
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid
  • the Lewis acid is selected from Aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the fifth aspect of the present invention provides an intermediate compound of formula V of hexahydrofuro[2,3-b]-3-ol, the structural formula is as follows:
  • R 1 and R 2 are hydrogen or hydroxy protecting groups
  • R 3 is alkyl, acyl, ether, ester or aryl
  • X is oxygen, sulfur or nitrogen.
  • the hydroxy protecting group is alkyl, silyl, C 2-11 acyl, C 4-9 cycloalkenyl, aryl, aralkyl, aroyl, phenyl, substituted phenyl, C 2-11 Ether group, C 2-11 ester group
  • the silyl group is a tetramethylsilyl group, a trimethylsilyl group, a triethylsilyl group, a tri-n-butylsilyl group, and a tert-butyldimethylsilyl group
  • the alkyl group is a C 1 -C 8 alkyl group
  • the aryl group is a phenyl group, a furyl group, a thienyl group or an indolyl group
  • the sixth aspect of the present invention provides a preparation method of hexahydrofuro[2,3-b]-3-ol formula VI, which is prepared by cyclization reaction of an intermediate compound of formula V'in the presence of an acid,
  • R 2 , R 3 , and X are the same as above;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid.
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the seventh aspect of the present invention provides a method for preparing hexahydrofuro[2,3-b]-3-ol formula VI, which is prepared by deprotecting an intermediate compound of formula V under acid, alkali or metal catalyst conditions.
  • the V'compound is prepared from the compound of formula V'through a cyclization reaction in the presence of an acid,
  • R 1 , R 2 , R 3 , and X are the same as above;
  • the base in the deprotection step is an organic base or an inorganic base
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the acid in the cyclization reaction step is an organic acid, an inorganic acid or a Lewis acid;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, Sulfuric acid, phosphoric acid, and Lewis acid are selected from aluminum chloride, ferric chloride, boron trifluoride, and niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the eighth aspect of the present invention provides a method for preparing hexahydrofuro[2,3-b]-3-ol formula VI.
  • a compound of formula V is prepared by condensation reaction of a compound of formula I in the presence of an acid.
  • the compound is prepared by deprotection in the presence of acid, base or metal catalyst to obtain the compound of formula V', and then prepared from the compound of formula V'by cyclization reaction in the presence of acid,
  • R 1 , R 2 , R 3 , and X are the same as above.
  • the organic acid in the condensation reaction step is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzenesulfonic acid, m-nitrobenzoic acid, and the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, and sulfuric acid , Phosphoric acid, aluminum chloride, iron chloride, boron trifluoride, niobium pentachloride, preferably p-toluenesulfonic acid;
  • the reaction temperature of the condensation reaction step is 10-50°C, preferably 15-35°C;
  • the organic base is selected from triethylamine, trimethylamine, diisopropylethylamine, diazabicyclo, pyridine, imidazole
  • the inorganic base is selected from potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, Sodium hydroxide, lithium hydroxide, sodium borohydride, lithium tetrahydroaluminum, red aluminum
  • the metal catalyst is selected from palladium reagents, nickel reagents, preferably sodium carbonate;
  • the reaction temperature of the deprotection step is 10-50°C, preferably 15-35°C;
  • the organic acid is selected from p-toluenesulfonic acid, dichloroacetic acid, dibromoacetic acid, m-nitrobenzene
  • the inorganic acid is selected from nitrous acid, hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid
  • the Lewis acid is selected from Aluminum chloride, ferric chloride, boron trifluoride, niobium pentachloride, preferably hydrochloric acid;
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • the reaction temperature of the cyclization reaction step is -10-20°C, preferably -5-15°C.
  • hexahydrofuro[2,3-b]-3-ol is prepared according to the above method, with low cost and mild reaction conditions, which provides another route suitable for industrialization for the preparation of the key intermediate of darunavir
  • the compound 30 aqueous solution was cooled by -2 to 5°C, concentrated hydrochloric acid (0.85 g, 8.5 mmol) was added, and the mixture was incubated at 0 to 5°C for about 5 to 8 hours, and sampled for GC detection. After the reaction, the pH was adjusted to 7-8 with sodium carbonate, and concentrated to dryness under reduced pressure at 50-70°C to obtain an oily substance. Add ethyl acetate and stir, filter, rinse the filter cake with ethyl acetate, and collect the filtrate. Concentrate under reduced pressure until no liquid flows out to obtain 0.95 g of oily compound 40 with a yield of 90.4% and a GC purity of 87.5%.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

La présente invention se rapporte au domaine de la synthèse pharmaceutique, et concerne en particulier un procédé de préparation d'un dérivé d'hexahydrofurofuranol et d'un intermédiaire du dérivé, ainsi qu'un procédé de préparation associé. Le procédé de préparation comprend une réaction de condensation, une déprotection et une réaction de cyclisation, comme le montre la formule (A), dans laquelle R 1 et R 2 représentent des groupes protecteurs d'hydrogène ou d'hydroxyle, R 3 représente un groupe alkyle, un groupe acyle, un groupe éther, un groupe ester ou un groupe aryle, et X représente oxygène, soufre ou azote. Dans le procédé de préparation du dérivé d'hexahydrofurofuranol, une réaction de condensation est effectuée sur le composé de formule I, de telle sorte qu'un produit peut être préparé avec une pureté optique très élevée. Le procédé de préparation permet la commercialisation de la production de l'intermédiaire clé, (3R,3aS,6aR)-hexahydrofuro [2,3-b]-3-ol, pour la préparation de Darunavir, et est un moyen très économique approprié pour la production industrielle.
PCT/CN2020/104791 2019-08-01 2020-07-27 Procédé de préparation d'un dérivé d'hexahydrofurofuranol et d'intermédiaire du dérivé et procédé de préparation associé WO2021018085A1 (fr)

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CN201910706770.0A CN112300186B (zh) 2019-08-01 2019-08-01 六氢呋喃并呋喃醇衍生物的制备方法、其中间体及其制备方法
CN201910706770.0 2019-08-01

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